Millions of people in the world suffer from inflammatory bowel disease (IBD). IBD is a collective term used to describe two gastrointestinal disorders of unknown etiology; Crohn's disease (CD) and ulcerative colitis (UC). Both diseases appear to result from the unrestrained activation of an inflammatory response in the intestine. Ulcerative colitis occurs in the large intestine, while Crohn's disease can involve any segment of the gastrointestinal tract. It has been suggested that the pathogenesis of IBD is multifactorial involving susceptibility genes and environmental factors. Although the causative triggers remain unclear, the role of a persistent and likely dysregulated mucosal immune response is central to the pathogenesis of IBD. It remains unclear whether the persistent inflammation, an intrinsic feature of IBD, reflects a primary aberration in mucosal response or results from an inappropriate persistent stimulation.
The course and prognosis of IBD varies widely. For most patients, it is a chronic condition with symptoms lasting for months to years. IBD is most commonly diagnosed in young adults, but can occur at any age. The clinical symptoms of IBD include intermittent rectal bleeding, fever, abdominal pain, and diarrhea, which may range from mild to severe. Additional common signs of IBD are anemia and weight loss. 10 to 15% of all IBD patients will require surgery over a ten year period. Protracted IBD is a risk factor for colon cancer, and the risk begins to rise significantly after eight to ten years of IBD.
Bowel disorders such as IBD are a significant medical problem, and improved methods of treatment are necessary as no completely satisfactory treatments are currently available.
The first line therapy that often is used for treatment of IBD is 5-aminosalicylic acid (5-ASA). A key to successful treatment is to deliver a high concentration of 5-ASA to the site of inflammation. However, when 5-ASA is administered orally without a carrier or protector, it is nearly completely systemically absorbed in the proximal small intestine prior to reaching the affected area, and is extensively metabolized in intestinal epithelial cells and the liver; it is then excreted in the urine, which may predispose patients to the development of a nephrotic syndrome as a side effect. Therefore, strategies to “protect” orally administered 5-ASA from absorption until it reaches the colon have been developed. These strategies include the use of prodrug, delayed-release formulations (coat the drug with polymers), controlled-release formulations (formulate the 5-ASA as ethylcellulose-coated microgranules), and, more recently, sophisticated formulations that combine both delayed-release and sustained-release mechanisms.
Various strategies have been proposed for targeting orally administered drugs to the colon, including: covalent linkage of a drug with a carrier, including those that enhance stability as well as increasing hydrophilicity; coating with pH-sensitive polymers; formulation of timed released systems; exploitation of carriers that are degraded specifically by colonic bacteria; bioadhesive systems; and osmotic controlled drug delivery systems. Various prodrugs (sulfasalazine, ipsalazine, balsalazide, and olsalazine) have been developed that are aimed to deliver 5-aminosalicylic acid (5-ASA) for localized chemotherapy of inflammatory bowel disease (IBD). Microbially degradable polymers, especially azo-crosslinked polymers, have been investigated for use as coatings for drugs targeted to the colon. Certain plant polysaccharides such as amylose, inulin, pectin, and guar gum remain unaffected in the presence of gastrointestinal enzymes and have been explored as coatings for drugs for the formulation of colon-targeted drug delivery systems. Additionally, combinations of plant polysaccharides with crustacean extract, including chitosan or derivatives thereof, are proving of interest for the development of colonic delivery systems.
The concept of using pH as a trigger to release a drug in the colon is based on the pH conditions that vary continuously down the gastrointestinal tract (GIT). Time-dependent drug delivery systems have been developed that are based on a principle of preventative release of drug until 3-hours after leaving the stomach. Redox sensitive polymers and bioadhesive systems have also been exploited to deliver the drugs into the colon. Other systems for drug delivery to the colon, pH-dependent systems, exploit the generally accepted view that pH of the human GIT increases progressively from the stomach (pH 1-which increases to during digestion), small intestine (pH 6-7) at the site of digestion and it increases to 7-8 in the distal ileum. The coating of pH-sensitive polymers to the tablets, capsules or pellets provides delayed release and protects the active drug from gastric fluid. The polymers used for colon targeting, however, should be able to withstand the lower pH values of the stomach and of the proximal part of the small intestine and also be able to disintegrate at the neutral or slightly alkaline pH of the terminal ileum and preferably at the ileocecal junction.
Lorenzo-Lamosa et al. (Design of microcncapsulated chitosan microspheres for colonic drug delivery. J Control Rel, 52: 109-118, 1998) prepared and demonstrated the efficacy of a system, which combines specific biodegradability and pH dependent release behaviour. The system consists of chitosan microcores entrapped within acrylic microspheres containing diclofenac sodium as a model drug. The drug was effectively entrapped within the chitosan microcores using spray drying and then microencapsulated into Eudragit™ L-100 and Eudragit™ S-100 acrylic polymers using an oil-in-oil solvent evaporation method. Release of the drug from chitosan multireservoir system was adjusted by changing the chitosan molecular weight or the type of chitosan salt. Furthermore, by coating the chitosan microcores with Eudragit™, perfect pH-dependent release profiles were attained. Similarly, melt extrusion of a drug with various Eudragit™ polymers in the presence or absence of chitosan, gelling agents or the like has the potential to enable colon-specific release.
Other suitable polymers that are slightly permeable to the active ingredient and water, and exhibit a pH-dependent permeability, include, but are not limited to, EUDRAGIT™ RL, EUDRAGIT™ RS, EUDRAGIT™ L, EUDRAGIT™ S, and EUDRAGIT™ E. See also Dressman, J. B., Amidon, C., Reppas, C. and Shah, V. P., Dissolution testing as a prognostic tool for oral drug absorption: Immediate release dosage forms, Pharm Res, 15: 11-22, 1998.
Polysaccharides, which retain their integrity because they are resistant to the digestive action of gastrointestinal enzymes also have been proposed for encapsulating drugs for colonic drug delivery. The matrices of polysaccharides are assumed to remain intact in the physiological environment of stomach and small intestine but once they reach in the colon, they are acted upon by the bacterial polysaccharidases and this action results in the degradation of the matrices. This family of natural polymers has an appeal to the area of drug delivery as it is comprised of polymers with a large number of derivatizable groups, a wide range of molecular weights, varying chemical compositions, and for the most part, a low toxicity and biodegradability, yet a high stability. The most favourable property of these materials is that they are already approved as pharmaceutical excipients. A large number of polysaccharides such as amylose, guar gum, pectin, chitosan, inulin, cyciodextrins, chondroitin sulphate, dextrans and locust bean gum, as well as modifications thereof, have been investigated for their use in colon-targeted drug delivery systems. The most important fact in the development of polysaccharide derivatives for colon targeted drug delivery is the selection of a suitable biodegradable polysaccharide. As these polysaccharides are usually soluble in water, they must be made water insoluble by crosslinking or hydrophobic derivatisation.
Guar gum is hydrophilic in nature and swells in cold water, forming viscous colloidal dispersions, or sols. This gelling property retards release of the drug from the dosage form and renders it susceptible to degradation in the colonic environment. Homogenized and diluted feces from a human source were incubated with the guar gum to investigate the degradation of the polysaccharide sol by intestinal microflora. It produced a rapid decrease in viscosity and an increase in pH (i.e. became more basic) while no such results were observed when it was incubated with autoclaved fecal homogenates. Guar gum was crosslinked with increasing amounts of trisodium trimetaphosphate to reduce its swelling properties for use as a vehicle in oral delivery formulations. As a result of the crosslinking procedure guar gum lost its non-ionic nature and became negatively charged. This was demonstrated by methylene blue adsorption studies and swelling studies in sodium chloride solutions with increasing concentrations in which the hydrogels' network collapsed (Gliko-Kabir, I., Yagen, B., Penhasi, A. and Rubinstein, A., Phosphated crosslinked guar for colon-specific drug delivery. I. Preparation and physicochemical characterization. J Control Rel, 63: 121-127, 2000). Crosslinked guar gum products were analysed to check the efficacy as a colon-specific drug carrier and it was found that the product which was crosslinked with 0.1 molar equivalent of trisodium trimetaphosphate was able to prevent the release of 80% of its hydrocortisone load for at least hours in PBS (pH 6.4). When a mixture of α-galactosidase and β-mannanase was added to the buffer solution, an enhanced release was observed. In vivo degradation studies in the rat caecum showed that despite the chemical modification of guar gum, it retained its enzyme-degrading properties in a crosslinker concentration dependent manner. A novel tablet formulation for oral administration using guar gum as the carrier and indomethacin as a model drug has been investigated for colon targeted drug delivery using in vitro methods. Drug release studies under conditions simulating the gastrointestinal transit have shown that guar gum protects the drug from being released completely in the physiological environment of stomach and small intestine. Studies in pH 6.8 PBS containing rat caecal contents have demonstrated the susceptibility of guar gum to the colonic bacterial enzyme action with consequent drug release (Rama Prasad, Y. V., Krishnaiah, Y. S. R. and Satyanarayana, S., In vitro evaluation of guar gum as a carrier for colon-specific drug delivery. J Control Rel, 51: 281-287, 1998). Colon-specific drug delivery also has been proposed using dried amylose films to encapsulate pharmaceutical formulations. Amylose, one of the major fractions of starch, possesses the ability to form films through gelation, when prepared under appropriate conditions. The microstructure of the film is potentially resistant to the action of pancreatic α-amylase but is digested by amylases of the colonic microflora. However, under simulated gastrointestinal conditions, coatings made solely of amylose will become porous and allow drug release. Incorporation of insoluble polymers into the amylose film, to control amylose swelling, provides a solution to this problem. A range of cellulose and acrylate based copolymers were assessed, of which a commercially available ethylcellulose (Ethocel) was found to control the swelling most effectively. The in vitro dissolution of various coated pellets under simulated gastric and small intestinal conditions, using commercially available pepsin and pancreatin was determined and demonstrated the resistance of the amylose-Ethocel coat (1:4) to such conditions over a period of 12 h (Milojevic, S., Newton, J. M., Cummings, J. H., Gibson, G. R., Botham, R. L., Ring, S. C., Stoekham, M. and Allwood, M. C., Amylose as a coating for drug delivery the colon: Preparation and in vitro evaluation using 5-aminosalicylic acid pellets. J Control Rel, 38: 75-84, 1996).
Chitosan is a high molecular weight polycationic polysaccharide derived from naturally occurring chitin by alkaline deacetylation. Chitosan has favourable biological properties such as nontoxicity, biocompatibility, and biodegradability. Similar to other polysaccharides, it also undergoes degradation by the action of colonic microflora, and hence poses its candidature for colon targeted drug delivery. Tozaki et al. (Tozaki, H., Odoriba, T., Okada, N., Fujita, T., Terabe, A., Suzuki, T., Okabe, S., Mumishi, S, and Yamamoto, A., Chitosan capsules for colon-specific drug delivery: enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats. J Control Rel, 82, 51-61, 2002) developed colon-specific insulin delivery with chitosan capsules. In vitro drug release experiments from chitosan capsules containing 5(6)-carboxyfluorescein (CF) were carried out by a rotating basket method with slight modifications. The intestinal absorption of insulin was evaluated by measuring the plasma insulin levels and its hypoglycaemic effects after oral administration of the chitosan capsules containing insulin and additives. Little release of CF from the capsules was observed in an artificial gastric juice (pH 1), or in an artificial intestinal juice (pH 7). However, the release of CF was markedly increased in the presence of rat caecal contents. This group further evaluated colon-specific insulin delivery using chitosan capsules. It was found that these were stable in the stomach and small intestine but degraded by micro-organisms in rat caecal contents upon entering into the colon, proving their utility as carriers for colon targeted drug delivery of peptide and non-peptide drugs.
Pectin, a predominantly linear polymer of mainly α-(1→4)-linked D-polygalacturonic acid residues, has been widely investigated as a colon-specific drug delivery entity. It can be broken down by pectinase enzymes produced by anaerobic bacteria of the colon and can control drug release by this principle (Atyabi et al, Carbohyd. Polymers, 2005, 61, 39-51). As pectin is water soluble, efficient colonic delivery requires that the solubility is controlled. Liu et al. (Liu et al, Biomaterials 2003, 24, 3333-3343) demonstrated promising drug delivery potential when pectin was combined with water-insoluble polymers. Previously, Wakerly et al. (Wakerly et al., Pharm. Res., 1996, 13 (8), 1210-1212) identified that a combination of ethylcellulose and pectin could provide protection of a drug in the upper GI tract while allowing enzymatic breakdown and drug release in the colon. Wei et al. (Wei et al., PDA Journal of Pharmaceutical Science and Technology, Vol 61, No. 2, March-April 2007, 121-130) demonstrated that colon-specific controlled release of the water-soluble anticancer agent, 5-fluorouracil, was possible when incorporated into pellets that were coated with various proportions of pectin and ethycellulose (Surlease®).
Redox potential is an expression of the total metabolic and bacterial activity in the colon and it is believed to be insensitive to dietary changes. The mean redox potential in proximal small bowel is −67±90 mV, in the distal small bowel is −196±97 mV and in the colon is −145±72 mV. Thus, microflora-induced changes in the redox potential can be used as a highly selective mechanism for targeting to the colon. Bragger et al. (Investigations into the azo reducing activity of a common colonic microorganism. Int J Pharm, 157: 61-71, 1997) carried out investigations into the azo reducing activity, which could enlighten some factors affecting the bacterial reduction (cleavage) of azo compounds. A common colonic bacterium, Bacteroides fragilis, was used as test organism, and the reductions of azo dyes amaranth, Orange II, tartrazine, and a model azo compound, 4,4′-dihydroxyazobenzene, were studied. It was found that the azo compounds were reduced at different rates, and the rate of reduction could be correlated with the redox potential of the azo compounds. Disulfide compounds can also undergo degradation due to the influence of redox potential in the colon. Noncrosslinked redox-sensitive polymers containing an azo and/or a disulfide linkage in the backbone have been synthesised (Schacht, E. and Wilding, I. R., Process for the preparation of azo- and/or disulfide-containing polymers. Patent: WO 9111175).
The foregoing discussion of prior art derives primarily from U.S. patent publication 2010/0255087 to Coulter who proposed oral pharmaceutical compositions comprising mini-capsules containing one or more active pharmaceutical compounds in a liquid, semi-solid or solid core mini-capsule format, wherein the mini-capsules have release profiles intended to release the active pharmaceutical compound at one or more sites along the gastro-intestinal tract where absorption is maximized or therapeutic efficacy is maximized. More particularly, according to the '087 publication, the mini-capsules are formed of or have coatings formed of materials that are sensitive to one or more pH, time, thickness, erosion and bacterial breakdown to achieve a desired release of active pharmaceutical agents along the gastro-intestinal tract.